Abstract While opioid use in the general population has received significant media and scholarly attention in recent years, very little research exists on opioid use among homeless or street-involved youth. Homeless youth have a much higher rate of substance use than non-homeless peers with evidence suggesting that homeless youth have the highest rates of opioid use among youth subgroups in the country (Brands et al., 2005); heroin using homeless youth also appear to have the highest rates of IV drug use and HIV (Rhoades et al., 2014). Given the high rates of opioid use, exposure to violence, mental and physical health challenges, and high rates of mortality in homeless youth, it is surprising that no study to date utilizes a randomized controlled design to test prevention of opioid and other drug use among this vulnerable population. Even among those receiving risk reduction interventions, lack of stable housing appears to be a barrier to reducing risk behaviors (DesJarlais et al., 2007). Resolution of youth homelessness through housing and prevention services, often referred to as ?Housing First?, as proposed in the current study, has great potential to reduce the likelihood for the development of an opioid use disorder as well as other problem behaviors associated with living on the streets. However, only 20-30% of homeless youth samples report ever having stayed at a crisis shelter, 9% report having ever accessed mental health services, and 15% report ever having received substance use treatment (Ray, 2006) indicating a need to reach and engage youth in services that are feasible and acceptable. This study will provide essential information for researchers and providers on the efficacy of housing + opioid and related risk prevention services in an RCT on opioid use, how moderators affect the response, and mechanisms underlying change. Our intervention and hypotheses are guided by our conceptual model incorporating the biopsychosocial model (Fordyce et al., 1973) with social ecological systems theory (Bronfenbrenner, 1979) and Bandura?s Social-Cognitive Theory (1977; 1986). Interview, physiological, and self-report methods will be used for data gathering. Phase I (UG3) of the study includes a pilot study with 21 youth to assess initial efficacy, feasibility of recruitment and acceptability of the manualized housing + opioid and related risk prevention services. Upon meeting transition milestones, 240 youth will then be recruited for a larger randomized clinical trial testing housing + opioid and related risk prevention services versus opioid and related risk prevention services alone (Phase II, UH3). Follow-up will be conducted at 3, 6, 9 and 12-months post-baseline. The economic cost of each intervention will be determined to inform future providers and their funders. This project utilizes existing efficacious models of prevention to generate valuable new information critical to prevention services delivery for a special population of highly vulnerable youth. Because youth experiencing homelessness are at increased risk for a variety of adverse outcomes, the proposed intervention may produce substantial health-care benefits to the youths and society at large.